1,2,3,4,5,6-Hexahydroazepino[4,5-b]indoles containing arylsulfones at the 9-position

ABSTRACT

The present invention are substituted 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles (X) and unsubstituted 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles (XI) such as the compound of EXAMPLE 13 
                 
 
which are useful in treating depression, obesity and other CNS disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 09/613,843, filed 11, Jul. 2000, now U.S. Pat. No. 6,468,999 whichclaims the benefit of U.S. provisional Application Ser. No. 60/144,574,filed Jul. 19, 1999, under 35 USC 119(e)(i).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is substituted9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles (X) which areuseful for treating anxiety, depression and other CNS disorders inhumans and animals.

2. Description of the Related Art

U.S. Pat. No. 3,652,588 discloses6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles which were useful fortranquilizing and sedating mammals to suppress hunger in mammals. Thisdocument discloses that there can be substitution at the 9-position.However, those substituents are limited to hydrogen, alkyl, alkoxy andhalogen.

U.S. Pat. No. 3,839,357 discloses6-benzyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles which were usefulfor tranquilizing mammals. This document discloses that there can besubstitution at the 9-position. However, those substituents are limitedto hydrogen, alkyl, alkoxy and halogen.

U.S. Pat. No. 3,676,558 discloses6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles which were useful tosuppress hunger in mammals. This document discloses that there can besubstitution at the 9-position. However, it is limited to hydrogen,alkyl, alkoxy and halogen.

SUMMARY OF INVENTION

Disclosed is a 9-arylsulfone of the formula (XII)

where R₃ is:

-   -   (1) —H,    -   (2) C₁-C₄ alkyl,    -   (3) C₀-C₄ alkyl-φ where the —φ substituent is optionally        substituted with 1 or 2        -   (a) —F, —Cl, —Br, —I,        -   (b) —O—R₃₋₁ where R₃₋₁ is:            -   —H,            -   C₁-C₄ alkyl,            -   —φ,        -   (c) —CF₃,        -   (d) —CO—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are —H and C₁-C₄            alkyl, and where R₃₋₂ and R₃₋₃ are taken with the attached            nitrogen atom to form a ring selected from the group            consisting of 1-pyrrolidinyl, 1-piperazinyl and            1-morpholinyl,        -   (e) —NH—SO₂—R₃₋₄ where R₃₋₄ is —H and C₁-C₄ alkyl,        -   (f) —NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are as defined above,        -   (g) —NR₃₋₄—CO—R₃₋₄ where R₃₋₄ is as defined above,        -   (h) —SO₂—NR₃₋₂R₃₋₃ where R₃₋₂ and R₃₋₃ are as defined above,        -   (i) —C≡N,        -   (j) —NO₂,            where R_(N) is:    -   (1) —H,    -   (2) C₁-C₄ alkyl,    -   (3) C₀-C₄ alkyl-φ where the —φ substituent is optionally        substituted with 1 or 2        -   (a) —F, —Cl, —Br, —I,        -   (b) —O—R_(N-1) where R_(N-1) is            -   —H,            -   C₁-C₄ alkyl,            -   —φ,        -   (c) —CF₃,        -   (d) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are —H and            C₁-C₄ alkyl, and where R_(N-2) and R_(N-3) are taken with            the attached nitrogen atom to form a ring selected from the            group consisting of 1-pyrrolidinyl, 1-piperazinyl and            1-morpholinyl,        -   (e) —NH—SO₂—R_(N-4) where R_(N-4) is —H and C₁-C₄ alkyl,        -   f) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined            above,        -   (g) —NR_(N-4)—CO—R_(N-4) where R_(N-4) is as defined above,        -   (h) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined above,        -   (i) —C≡N,        -   (j) —NO₂,            where R_(X) is:    -   (1) —H    -   (2) —F, —Cl, —Br, —I,    -   (3) —O—R_(X-1) where R_(X-1) is:        -   —H,        -   C₁-C₄ alkyl,        -   —φ,    -   (4) —CF₃,    -   (5) —CO—NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are —H and        C₁-C₄ alkyl, and where R_(X-2) and R_(X-3) are taken with the        attached nitrogen atom to form a ring selected from the group        consisting of 1-pyrrolidinyl, 1-piperazinyl and 1-morpholinyl,    -   (6) —NH—SO₂—R_(X-4) where R_(X-4) is —H and C₁-C₄ alkyl,    -   (7) —NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are as defined        above,    -   (8) —NR_(X-4)—CO—R_(X-4) where R_(X-4) is as defined above,    -   (9) —SO₂—NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are as        defined above,    -   (10) —C≡N,    -   (11) —NO₂;        where R₉ is:    -   (1) —H,    -   (2) —F, —Cl,    -   (3) C₁-C₄ alkyl,    -   (4) C₁-C₃ alkoxy,    -   (5) —CF₃,    -   (6) C₀-C₄ alkyl-φ where the —φ substituent is optionally        substituted with 1 or 2        -   (a) —F, —Cl, —Br, —I,        -   (b) —O—R₉₋₁ where R₉₋₁ is:            -   —H,            -   C₁-C₄ alkyl,            -   —φ,        -   (c) —CF₃,        -   (d) —CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are —H and C₁-C₄            alkyl, and where R₉₋₂ and R₉₋₃ are taken with the attached            nitrogen atom to form a ring selected from the group            consisting of 1-pyrrolidinyl, 1-piperazinyl and            1-morpholinyl,        -   (e) —NH—SO₂—R₉₋₄ where R₉₋₄ is —H and C₁-C₄ alkyl,        -   (f) —NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,        -   (g) —NR₉₋₄—CO—R₉₋₄ where R₉₋₄ is as defined above,        -   (h) —SO₂—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,        -   (i) —C≡N,        -   (j) —NO₂    -   (7) —OR₉₋₁ where R₉₋₁ is as defined above,    -   (8) —CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,    -   (9) —NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above,    -   (10) —NH—SO₂—R₉₋₄ where R₉₋₄ is as defined above,    -   (11) —NH—CO₂—R₉₋₂ where R₉₋₂ is as defined above,        and pharmaceutically acceptable salts thereof.

Also disclosed are compounds which are intermediates in the productionof the 9-arylsulfones (XII), the thio ethers of formula (III), theamines of formula (IV), the hydrazines of formula (V), the compounds offormula (VII) and the protected 9-arylsulfones of formula (VIII) wherePG is selected from the group consisting of φ—CH₂—, φ—CO—, φ—CH₂—CO₂—and —CO—O—C(CH₃)₃ and where R₉ and R_(x) are as defined above.

Further disclosed is a method of treating a human who has a conditionselected from the group consisting of anxiety, depression,schizophrenia, stress related disease, panic, a phobia, obsessivecompulsive disorder, obeisity, post-traumatic stress syndrome who is inneed of such treatment which comprises administering an effective amountof a 9-arylsulfone of the formula (XII).

DETAILED DESCRIPTION OF THE INVENTION

The unsubstituted 9-arylsulfones (IX) and substituted 9-arylsulfones (X)are both prepared by means known to those skilled in the art. The term9-arylsulfones (XII) includes both the unsubstituted 9-arylsulfones(IX), where R₃ is —H and substituted 9-arylsulfones (X) where R₃ is ≠ to—H. The process of preparation can be viewed as being in two parts. Thefirst part is the production of the appropriately substituted hydrazone(V), see CHART A. The second part is the coupling and reaction of theappropriately substituted hydrazone (V) with the 1-protectedhexahydro-4H-azepine-4-one (VI) to give the intermediate (VII) and itstransformation to the unsubstituted 9-arylsulfone (IX), see CHART B.

The appropriately substituted thiols (I) are either known to thoseskilled in the art or can be readily prepared from known startingmaterials by means well known to those skilled in the art. There can beeither one or two R₉ substituents and R₉ includes —H, —F, —Cl, C₁-C₃alkyl, C₁-C₃ alkoxy and —CF₃; it is preferred that R₉ is —H, —F, —Cl, C₁alkyl, C₁ alkoxy, and —CF₃ and when F— it is preferred that it be in the4- or p-position. It is preferred that the R₉ substituent be in eitherthe 3- or 4-position.

The appropriately substituted thiol (I) is coupled with theappropriately substituted 4-chloro-1-nitrobenzene (II) by known means toproduce the thioether (III). There can be either one or two R_(x)groups. If R_(x) is other than —H, it should be part of the4-chloro-1-nitrobenzene (II) so that it will become part of the finalunsubstituted 9-arylsulfone (IX) when it is formed. It is most difficultto add the R_(x) substitutent (other than —H) to the unsubstituted9-arylsulfone (IX) once it is formed. Therefore, the R_(x) group shouldbe part of the appropriately substituted 4-chloro-1-nitrobenzene (II)when it is reacted with the thiol (I). R_(x) includes of —H, —F and —Cl;it is preferred that R_(x) is —H. The thioether (III) is then oxidizedwith hydrogen peroxide (30%) followed by reduction with rhodium oncarbon (5%), all of which is known to those skilled in the art, toproduce the amine (IV). The amine (IV) is then diazotized by (sodium)nitrite and (hydrochloric) acid followed by reduction with tinchloride/water to give the corresponding hydrazine (V).

The second part of the reaction, is well known to those skilled in theart, see U.S. Pat. Nos. 3,652,588, 3,676,558 and 3,839,357. The onlydifference between the process in those patents and that here is thearylsulfone substituent at the 9-position. That substituent is alreadyin place in the hydrazine (V) prior to the reaction of the 9-arylsulfonehydrazine (V) with the 1-protected hexahydro-4H-azepine-4-one (VI) toproduce the correspondingly substituted intermediate (VII). Suitableprotecting groups (PG) include φ—CH₂—, φ—CO—, φ—CH₂—CO₂— and—CO—O—C(CH₃)₃; it is preferred that the protecting group be φ—CH₂— orφ—CO—. The cyclization of the intermediate (VII) to the correspondingprotected arylsulfone (VIII) and then the deprotection to theunsubstituted 9-arylsulfone (IX) all follow known methods. Theprotecting groups (PG) are readily removed by means well known to thoseskilled in the art. The unsubstituted 9-arylsulfone (IX) can then besubstituted at the C3-position (R₃, ring nitrogen atom) as well as onthe indole nitrogen (R_(N)) as is known to those skilled in the art.Alternatively, arylsulfone (VIII) can be alkylated with the desiredR_(N)—X substituent to give the protected indole (XI) which then isdeprotected to give the desired substituted 9-arylsulfone (X). Useful R₃groups include of —H and C₁-C₂ alkyl; it is preferred that R₃ be —H.Useful R_(N) groups include of —H and C₁-C₄ alkyl; it is preferred thatR_(N) is —H, C₁ alkyl and C₂ alkyl. The invention here is not theprocess chemistry but rather the novel products produced.

The preferred protecting group for the intermediates (VI), (VII) and(VIII) are benzyl and benzamide though other groups are operable as isknown to those skilled in the art.

The 9-arylsulfones (XI) are amines, and as such form acid addition saltswhen reacted with acids of sufficient strength. Pharmaceuticallyacceptable salts include salts of both inorganic and organic acids. Thepharmaceutically acceptable salts are preferred over the correspondingfree amines since they produce compounds which are more water solubleand more crystalline. The preferred pharmaceutically acceptable saltsinclude salts of the following acids methanesulfonic, hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric,fumaric, maleic, CH₃—(CH₂)_(n)—COOH where n is 0 thru 4,HOOC—(CH₂)_(n)—COOH where n is as defined above.

The 9-arylsulfones (XI) of the present invention are useful to treatanxiety, depression, schizophrenia, stress related disease, panic, aphobia, obsessive compulsive disorder, obeisity, post-traumatic stresssyndrome and other CNS disorders. It is preferred that the 9-arylsulfones (XI) be used to treat anxiety for depression. To treat thesediseases the 9-arylsulfones (XI) are administered orally, sublingually,transdermally or parenterally to provide a dosage of about 0.1 to about50 mg/kg/day. It is preferred that the dosage range be from about 0.1 toabout 10 mg/kg/day. The 9-arylsulfones (XI) can be administered individed doses either two, three or four times daily. It is preferredthat the 9-arylsulfones (XI) be administered orally.

The exact dosage and frequency of administration depends on theparticular 9-arylsulfone(s) used, the particular disease being treated,the severity of the disease being treated, the age, weight, generalphysical condition of the particular patient, other medication theindividual may be taking as is well known to those skilled in the artand can be more accurately determined by measuring the blood level orconcentration of the 9-arylsulfone (XI) in the patient's blood and/orthe patient's response to the particular condition being treated.

DEFINITIONS AND CONVENTIONS

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

I. Conventions for Formulas and Definitions of Variables

The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, “Z₁” or “R_(i)” where “i” is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds. For example, a group Z₁ would represent a bivalentvariable if attached to the formula CH₃—C(═Z₁)H. Groups R_(i) and R_(j)would represent monovalent variable substituents if attached to theformula CH₃—CH₂— —C(R_(i))(R_(j))—H. When chemical formulas are drawn ina linear fashion, such as those above, variable substituents containedin parentheses are bonded to the atom immediately to the left of thevariable substituent enclosed in parenthesis. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variable substituents is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom. Also, for any molecule with an established system of carbonatom numbering, such as steroids, these carbon atoms are designated asC_(i), where “i” is the integer corresponding to the carbon atom number.For example, C₆ represents the 6 position or carbon atom number in thesteroid nucleus as traditionally designated by those skilled in the artof steroid chemistry. Likewise the term “R₆” represents a variablesubstituent (either monovalent or bivalent) at the C₆ position.

Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol “—” in general representsa bond between two atoms in the chain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃represents a 2-substituted-1-methoxypropane compound. In a similarfashion, the symbol “═” represents a double bond, e.g.,CH₂═C(R_(i))—O—CH₃, and the symbol “°” represents a triple bond, e.g.,HC°C—CH(R_(i))—CH₂—CH₃. Carbonyl groups are represented in either one oftwo ways: —CO— or —C(═O)—, with the former being preferred forsimplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments canbe represented in a linear fashion. Thus, the compound4-chloro-2-methylpyridine can be represented in linear fashion byN*═C(CH₃)—CH═CCl—CH═C*H with the convention that the atoms marked withan asterisk (*) are bonded to each other resulting in the formation of aring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinylcan be represented by —N*—(CH₂)₂—N(C₂H₅)—CH₂—C*H₂.

A rigid cyclic (ring) structure for any compounds herein defines anorientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to a carbon atom which ispart of a cyclic system, —C(X₁)(X₂)— the two substituents may be ineither an axial or equatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above the other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is “below” anothersubstituent (X₂) will be identified as being in the alpha (α)configuration and is identified by a broken, dashed or dotted lineattachment to the carbon atom, i.e., by the symbol “ - - - ” or “ . . .”. The corresponding substituent attached “above” (X₂) the other (X₁) isidentified as being in the beta (β) configuration and is indicated by anunbroken or solid line attachment to the carbon atom.

When a variable substituent is bivalent, the valences may be takentogether or separately or both in the definition of the variable. Forexample, a variable R_(i) attached to a carbon atom as —C(═R_(i))— mightbe bivalent and be defined as oxo or keto (thus forming a carbonyl group(—CO—) or as two separately attached monovalent variable substituentsa-R_(i-j) and β-R_(i-k). When a bivalent variable, R_(i), is defined toconsist of two monovalent variable substituents, the convention used todefine the bivalent variable is of the form “a-R_(i-j):β-R_(i-k)” orsome variant thereof. In such a case both a-R_(i-j) and β-R_(i-k) areattached to the carbon atom to give —C(a-R_(i-j))(β-R_(i-k))—. Forexample, when the bivalent variable R₆, —C(═R₆)— is defined to consistof two monovalent variable substituents, the two monovalent variablesubstituents are a-R₆₋₁:β-R₆₋₂, . . . a-R₆₋₉:β-R₆₋₁₀, etc, giving—C(a-R₆₋₁)(β-R₆₋₂)—, . . . —C(a-R₆₋₉)(β-R₆₋₁₀)—, etc. Likewise, for thebivalent variable R₁₁, —C(═R₁₁)—, two monovalent variable substituentsare a-R₁₁₋₁:β-R₁₁₋₂. For a ring substituent for which separate a and βorientations do not exist (e.g. due to the presence of a carbon carbondouble bond in the ring), and for a substituent bonded to a carbon atomwhich is not part of a ring the above convention is still used, but thea and β designations are omitted.

Just as a bivalent variable may be defined as two separate monovalentvariable substituents, two separate monovalent variable substituents maybe defined to be taken together to form a bivalent variable. Forexample, in the formula —C₁(R_(i))H—C₂(R_(j))H—(C₁ and C₂ definearbitrarily a first and second carbon atom, respectively) R_(i) andR_(j) may be defined to be taken together to form (1) a second bondbetween C₁ and C₂ or (2) a bivalent group such as oxa (—O—) and theformula thereby describes an epoxide. When R_(i) and R_(j) are takentogether to form a more complex entity, such as the group —X—Y—, thenthe orientation of the entity is such that C₁ in the above formula isbonded to X and C₂ is bonded to Y. Thus, by convention the designation “. . . R_(i) and R_(j) are taken together to form —CH₂—CH₂—O—CO— . . . ”means a lactone in which the carbonyl is bonded to C₂. However, whendesignated “ . . . R₁ and R_(i) are taken together to form—CO—O—CH₂—CH₂-the convention means a lactone in which the carbonyl isbonded to C₁.

The carbon atom content of variable substituents is indicated in one oftwo ways. The first method uses a prefix to the entire name of thevariable such as “C₁-C₄”, where both “1” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, “C₁-C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂-C₄ alkoxycarbonyl describes a group CH₃—(CH₂)_(n)—O—CO— where nis zero, one or two. By the second method the carbon atom content ofonly each portion of the definition is indicated separately by enclosingthe “C_(i)-C_(j)” designation in parentheses and placing it immediately(no intervening space) before the portion of the definition beingdefined. By this optional convention (C₁-C₃)alkoxycarbonyl has the samemeaning as C₂-C₄ alkoxy-carbonyl because the “C₁-C₃” refers only to thecarbon atom content of the alkoxy group. Similarly while both C₂-C₆alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)alkyl define alkoxyalkyl groupscontaining from 2 to 6 carbon atoms, the two definitions differ sincethe former definition allows either the alkoxy or alkyl portion alone tocontain 4 or 5 carbon atoms while the latter definition limits either ofthese groups to 3 carbon atoms.

When the claims contain a fairly complex (cyclic) substituent, at theend of the phrase naming/designating that particular substituent will bea notation in (parentheses) which will correspond to the samename/designation in one of the CHARTS which will also set forth thechemical structural formula of that particular substituent.

II. Definitions

All temperatures are in degrees Centigrade.

HPLC refers to high pressure liquid chromatography.

DMSO refers to dimethylsulfoxide.

DMF refers to dimethylformamide.

Saline refers to an aqueous saturated sodium chloride solution.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

IR refers to infrared spectroscopy.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (d) downfield from tetramethylsilane.

—φ refers to phenyl (C₆H₅).

MS refers to mass spectrometry expressed as m/e, m/z or mass/chargeunit. [M+H]⁺ refers to the positive ion of a parent plus a hydrogenatom. El refers to electron impact. CI refers to chemical ionization.FAB refers to fast atom bombardment.

HRMS refers to high resolution mass spectrometry.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Preparation 1 1-[4-(Phenylsulfonyl)phenyl]hydrazine (V)

A mixture of 4-chlorophenyl phenyl sulfone (10.1 g, 40.0 mmol),hydrazine mono-hydrate (30 mL), and triethylamine (4 drops) in ethyleneglycol (20 mL) is heated at 150° for 15 hr. Upon cooling, the mixture isdiluted with H₂O and filtered. The residual solid is washed with H₂Ountil the washings are neural (pH=6). This material is then trituratedwith methylene chloride and dried under reduced pressure at 50° to givethe title compound, IR (drift) 3282, 1586, 1514, 1306, 1291, 1158, 1145,1104, 996, 813, 756, 730, 717, 688 and 678 cm⁻¹; NMR (300 MHz, CDCl₃)7.70-7.85, 7.45-7.65, 6.79 and 4.22 δ; MS (EI) m/z 248 (M⁺), 125, 123,108, 107, 90, 80, 77, 63 and 51.

Preparation 2 1-[4-[(4-Fluorophenyl)sulfonyl]phenyl]hydrazine (V)

Step I: 4-Fluorophenyl-4-nitrophenyl sulfide (III)

A mixture of 4-fluorothiophenol (I, 2.08 g, 19.5 mmol),1-chloro-4-nitrobenzene (II, 3.39 g, 21.5 mmol), and potassium carbonate(5.40 g, 39.0 mmol) in acetonitrile (75 mL) is stirred at 20-25° undernitrogen for 16 hr. The mixture is diluted with H₂O (100 mL) andextracted into methylene chloride (3×100 mL). The extracts are driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to provide a quantitative yield of the desiredthioether, mp=84-90°; NMR (300 MHz, CDCl₃) 8.07, 7.45-7.60 and,7.05-7.25 δ.

Step II: 4-[(4-Fluorophenyl)sulfonyl]phenylamine (IV)

A hot mixture (100°) of 4-fluorophenyl 4-nitrophenyl sulfide (III, StepI, 1.91 g, 7.66 mmol) in glacial acetic acid (50 mL) is treated withhydrogen peroxide (30%, 2.60 mL), followed 20 min later by a secondportion of hydrogen peroxide (30%, 1.70 mL). The mixture continued toheat for an additional 30 min, and is then allowed to cool to 20-25°.The mixture is concentrated to near dryness and filtered, rinsing thesolid with H₂O. The solid is dried in a vacuum oven at 50° to give theintermediate sulfone, IR (drift) 1590, 1534, 1356, 1307, 1294, 1242,1166, 1156, 1109, 1101, 858, 839, 742, 687 and 665 cm⁻¹; NMR (300 MHz,CDCl₃) 8.35, 8.12, 7.95-8.05 and 7.15-7.30 δ; MS (EI) m/z 281 (M⁺), 159,143, 111, 95, 95, 83, 76, 74 and 51.

A mixture of 4-fluorophenyl 4-nitrophenyl sulfone (1.89 g, 6.72 mmol) inmethanol (80 mL) is treated with Rhodium on carbon (5%, 95 mg) andhydrogenated at 20 psi for 24 hr. The mixture is filtered, rinsing withmethylene chloride (2×100 mL) and methanol (100 mL). The filtrate isconcentrated to near dryness and refiltered, rinsing with minimalmethanol. The solid is dried in the vacuum oven at 50° to give thedesired amine, mp=204-205°: IR (drift) 3473, 3373, 1638, 1592, 1489,1303, 1294, 1285, 1231, 1159, 1144, 1107, 834, 713 and 689 cm⁻¹; NMR(300 MHz, CDCl₃) 7.80-7.95, 7.60-7.75, 7.13, 6.60-6.75 and 4.17 δ; MS(EI) m/z 251 (M⁺), 140, 108, 95, 92, 80, 65, 65, 63 and 51.

Step III: 1-[4-[(4-fluorophenyl)sulfonyl]phenyl]hydrazine (V)

A mixture of 4-[(4-fluorophenyl)sulfonyl]phenylamine (IV, Step II, 3.10g, 12.3 mmol) in concentrated hydrochloric acid (30 mL) at 0° is treatedwith sodium nitrite (934 mg, 13.5 mmol) in H₂O (15 mL). After 30 min,the mixture is treated with stannous chloride (5.57 g, 24.7 mmol) inconcentrated hydrochloric acid (15 mL). The mixture is stirred at 0° for1 hr, and then at 20-25° for 1 hr. The precipitate is collected andslurried in H₂O. The mixture is made basic (sodium hydroxide, 50%) andthe solid isolated. The material is partitioned between methylenechloride and saline. The organic layer is dried, filtered, andconcentrated under reduced pressure to give the title compound, NMR (300MHz, CDCl₃) 7.85-7.95, 7.74, 7.13, 6.85, 5.64 and 3.65 δ.

Example 1 9-(Phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

Step I: 1-Benzyl-4-azepanone N-[4-(phenylsulfonyl)phenyl]hydrazone (VII)

A mixture of 1-[4-(phenylsulfonyl)phenyl]hydrazine (V, PREPARATION 1,7.06 g, 28.4 mmol) and 4-benzylazapanone (VI, 5.78 g, 28.4 mmol) inethanol (130 mL) is treated with glacial acetic acid (8 drops) andheated at reflux for 1 hr. Upon cooling, the precipitate is collected,washed with ethanol and dried in the vacuum oven at 50° to give thedesired compound, mp=142-146°. The filtrate is concentrated and purifiedvia flash chromatography (ethyl acetate/heptane; 65/35) to provideadditional product as two regioisomers. Analytical data for one isomer:IR (drift) 1593, 1511, 1323, 1301, 1261, 1148, 1106, 1069, 833, 758,748, 735, 709, 689 and 600 cm⁻¹; NMR (300 MHz, CDCl₃) 7.85-7.95, 7.77,7.40-7.65, 7.15-7.35, 7.06, 3.65, 2.65-2.85, 2.55-2.65, 2.35-2.45 and,1.70-1.85; MS (EI) m/z 433 (M⁺), 186, 120, 108, 97, 96, 91, 82, 77, 65and 51. Analytical data for the slower eluting isomer: IR (drift) 1593,1509, 1324, 1296, 1285, 1264, 1148, 1106, 1085, 1069, 834, 735, 710, 688and 605 cm⁻¹; NMR (300 MHz, CDCl₃) 7.85-7.95, 7.70-7.85, 7.35-7.55,7.15-7.35, 7.06, 3.60, 2.55-2.75, 3.32-2.45 and 1.85-2.00; MS (EI) m/z433 (M⁺), 187, 186, 120, 108, 97, 91, 82, 77, 65 and 51.

Step II:3-Benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(VIII)

A mixture of 1-benzyl-4-azepanone N-[4-(phenylsulfonyl)phenyl]hydrazone(VII, Step I, 3.41 g, 7.86 mmol) and polyphosporic acid (4.78 g) ino-xylene (550 mL) is heated at 100° under nitrogen for 3 hr. Uponcooling, the xylene is decanted and the residual material partitionedbetween methylene chloride/methanol and sodium hydroxide (0.5 M). Thephases are separated and the aqueous layer is further extracted withmore methylene chloride/methanol (2×). The organic phases are combinedand dried over anhydrous magnesium sulfate, filtered, and concentratedunder reduced pressure to give an oil. The oil is purified by flashchromatography (Biotage 40M; ethyl acetate/heptane, 7/3) to give thedesired indole, mp=86-88°, dec; IR (drift) 3343, 2910, 1475, 1449, 1337,1301, 1146, 1131, 1090, 748, 731, 719, 698, 688 and 627 cm⁻¹; NMR (300MHz, CDCl₃) 8.10-8.20, 8.06, 7.96, 7.66, 7.25-7.55, 3.85 and 2.90-3.05δ; MS (EI) m/z 416 (M⁺), 296, 154, 146, 134, 134, 132, 120, 91 and 65.

Step III: 9-(Phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

A mixture of3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(VIII, Step II, 453 mg, 1.09 mmol) in methanol (50 mL) is treated withpalladium hydroxide (118 mg) and hydrogenated at 30 psi for 5 days. Themixture is filtered, rinsing with methanol and methylene chloride, andthe filtrate concentrated under reduced pressure to give an amorphoussolid. The material is purified by flash chromatography (Biotage 40M;methanol/methylene chloride, 5/95; methanol/methylene chloride/ammoniumhydroxide, 20/79/1) to give the title compound. Analytical data for thehydrochloride salt, mp=290-291.5°; IR (drift) 3382, 2751, 2698, 2689,2646, 2438, 1297, 1150, 1131, 1095, 801, 759, 722, 684 and 616 cm⁻¹; NMR(300 MHz, DMSO-d₆) 11.65, 7.35, 8.05-8.15, 7.85-7.95, 7.40-7.65,3.20-3.40 and 3.10-3.25 δ; MS (EI) m/z 326 (M⁺), 298, 297, 286, 285,284, 143 and 77; HRMS (FAB) calculated for C₁₈H₁₉N₂O₂S=327.1167, found327.1165.

Example 29-[(4-Fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

Following the general procedure of EXAMPLE 1 (Steps I-III) and makingnon-critical variations, 1-[4-[(4-fluorophenyl)sulfonyl]phenyl]hydrazine(V, PREPARATION 2) is converted to the title compound, mp=168°, dec.; IR(drift) 2923, 1590, 1491, 1475, 1336, 1308, 1287, 1236, 1147, 1131,1089, 837, 816, 749 and 683 cm⁻¹; NMR (300 MHz. CDCl₃) 8.05-8.15, 8.05,7.90-8.00, 7.55-7.65, 7.30-7.35, 7.12, 3.05-3.15 and 2.90-3.00 δ; HRMS(FAB) calculated for C₁₈H₁₈FN₂O₂S=345.1073, found 345.1087.

Example 39-[(4-Methylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

Following the general procedure of EXAMPLE 1 (Steps I-III) and makingnon-critical variations, 1-[4-[(4-methylphenyl)sulfonyl]phenyl]hydrazine(V, PREPARATION 2) is converted to the title compound, mp=125°, dec; IR(drift) 3027, 2921, 2830, 1475, 1453, 1336, 1298, 1287, 1150, 1130,1090, 812, 747, 682 and 658 cm⁻¹; NMR (300 MHz, CDCl₃) 8.12, 7.83,7.55-7.65, 7.20-7.35, 3.05-3.20, 2.90-3.05 and 2.36 δ; MS (EI) m/z 340(M⁺), 311, 298, 154, 144, 143, 115, 91, 91 and 65; HRMS (FAB) calculatedfor CH₁₉H₂₁N₂O₂S=341.1324, found 341.1311.

Example 49-[(4-Methoxyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

Following the general procedure of EXAMPLE 1, and making non-criticalvariations, 1-[4-[(4-methylphenyl)sulfonyl]phenyl]hydrazine (V,PREPARATION 2) is converted to the title compound, mp=139°, dec.; IR(drift) 2927, 2837, 1593, 1496, 1335, 1312, 1293, 1260, 1142, 1130,1092, 834, 802, 748 and 683 cm⁻¹; NMR (300 MHz, DMSO-d₆) 11.30,7.90-8.00, 7.75-7.85, 7.40-7.50, 7.30-7.40, 7.00-7.10, 3.77 and2.75-3.05; MS (EI) m/z 356 (M⁺), 327, 314, 155, 154, 143, 143, 115, 77and 57; HRMS (FAB) calculated for C₁₉H₂₁N₂O₃S=357.1273, found 357.1275.

Example 59-[(3-Fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

Following the general procedure of EXAMPLE 1, and making non-criticalvariations, 1-[4-[(3-fluorophenyl)sulfonyl]phenyl]hydrazine (V,PREPARATION 2) is converted to the title compound, mp=153-156°: IR(drift) 2926, 2867, 2855, 1474, 1311, 1296, 1225, 1151, 1129, 1082, 773,742, 698, 677 and 629 cm⁻¹; NMR (300 MHz, DMSO-d₆) 11.37, 8.00-8.10,7.70-7.80, 7.30-7.75 and 2.75-2.95 δ; MS (EI) m/z 344 (M⁺), 315, 302,154, 144, 143, 128, 128, 115 and 73; HRMS (FAB) calculated forC₁₈H₁₈FN₂O₂S=345.1073, found 345.1075.

Example 69-[(3-Methoxylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

Following the general procedure of EXAMPLE 1, and making non-criticalvariations, 1-[4-[(3-methoxyphenyl)sulfonyl]phenyl]hydrazine (V,PREPARATION 2) is converted to the title compound, mp=232-235°, dec.; IR(drift) 2976, 2963, 2832, 2805, 2770, 2739, 1475, 1303, 1248, 1151,1141, 746, 694, 682 and 629 cm⁻¹; NMR (300 MHz, DMSO-d₆) 11.63, 9.31,8.10-8.15, 7.35-7.60, 7.10-7.20, 3.79, 3.20-3.40 and 3.05-3.40 δ; MS(EI) m/z 356 (M⁺), 327, 314, 107, 74, 73, 59, 57, 57 and 56; MS (FAB)m/z 357 (MH⁺), 356, 328, 177, 155, 121, 103, 89; HRMS (FAB) calculatedfor C₁₉H₂₁N₂O₃S=357.1273, found 357.1277.

Example 79-[(4-Trifluoromethyphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

Following the general procedure of EXAMPLE 1, and making non-criticalvariations, 1-[4-[(4-trifluoromethylphenyl)sulfonyl]phenyl]hydrazine (V,PREPARATION 2) is converted to the title compound, mp=278-279°, dec.; IR(drift) 2773, 2756, 2732, 1321, 1306, 1178, 1156, 1133, 1122, 1108,1061, 844, 716, 623 and 618 cm⁻¹; NMR (300 MHz, DMSO-d₆) 8.05-8.20,7.90-8.00, 7.55-7.45, 7.45-7.55 and 3.05-3.40 δ; MS (EI) m/z 394 (M⁺),365, 352, 154, 143, 73, 71, 59, 58 and 57.

Example 86-Ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

Step I:3-Benzyl-6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

A 0° mixture of3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 1, Step II, 301 mg, 0.723 mmol) in dry DMF (5 mL) is treatedwith sodium hydride (60% in oil, 32 mg, 0.795 mmol), and allowed to warmto 20-25° over 1.5 hr. The mixture is then cooled (0°), treated withiodoethane (64 μL, 0.795 mmol) and allowed to slowly warm to 20-25°under nitrogen over 72 hr. The resultant mixture is diluted with ethylacetate (50 mL) and washed with H₂O (3×25 mL) and saline (25 mL). Theorganic layer is dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to give a solid. The solid ispurified via chromatography (20 g SG; ethyl acetate/heptane, 65/35) togive the indole as a solid, mp=188-191°; IR (drift) 1477, 1373, 1300,1289, 1157, 1148, 1094, 766, 756, 738, 728, 701, 694, 645 and 621 cm⁻¹;NMR (300 MHz, CDCl₃) 8.10-8.20, 7.90-8.05, 7.65-7.75, 7.20-7.50, 4.11,3.82, 2.85-3.05 and 1.27 δ; MS (EI) m/z 444 (M⁺), 326, 324, 312, 167,154, 132, 118, 96, 91 and 64.

Step II:6-Ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (X)

A mixture of3-benzyl-6-ethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Step I, 107 mg, 0.241 mmol) in methanol (20 mL, 1 drop concentratedhydrochloric acid) is treated with palladium on carbon (10%, 32 mg) andhydrogenated at 25 psi for 48 hr. The resulting mixture is filtered,rinsing with methanol and methylene chloride, and the filtrate isconcentrated to a solid. The solid is purified via chromatography (10 gSG; methanol/methylene chloride/ammonium hydroxide, 20/79/1) to give thetitle compound, mp=224°, dec.; IR (drift) 2982, 2935, 2743, 1473, 1449,1312. 1300, 1151, 1091, 819, 768, 728, 691, 647 and 623 cm⁻¹; NMR (300MHz, DMSO-d₆) 8.09, 7.85-7.95, 7.45-7.65, 4.20, 2.95-3.25 and 1.15 δ; MS(EI) m/z 354 (M⁺), 312, 170, 167, 153, 143, 114, 78, 76 and 51; HRMS(FAB) calculated for C₂₀H₂₃N₂O₂S=355.1480, found 355.1488.

Example 96-Ethyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

Following the general procedure of EXAMPLE 8, and making non-criticalvariations,3-benzyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 2) is converted to the title compound, mp=227-233°, dec.; IR(drift) 2972, 2834, 2755, 2713, 2679, 1589, 1490, 1471, 1312, 1293,1223, 1148, 1094, 715 and 693 cm⁻¹; MS (EI) m/z 372 (M⁺), 331, 330, 171,171, 154, 143, 143, 91 and 57; NMR (300 MHz, DMSO-d₆) 9.30, 8.18, 8.02,7.55-7.70, 7.41, 4.24, 3.10-3.40 and 1.19 δ; MS (FAB) m/z 373 (MH⁺),372, 371, 344 and 330; HRMS (FAB) calculated for C₂₀H₂₂FN₂O₂S=373.1386,found 373.1371.

Example 106-Methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

Following the general procedure of EXAMPLE 8, and making non-criticalvariations,3-benzyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 2) is converted to the title compound, mp>3000; IR (drift)2775, 1589, 1489, 1310, 1288, 1237, 1149, 1091, 841, 836, 805, 718, 667,639 and 605 cm⁻¹; NMR (300 MHz, DMSO-d₆) 9.51, 8.17, 8.01, 7.63, 7.41,3.72 and 3.10-3.45 δ.

Example 116-Methyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

Following the general procedure of EXAMPLE 8, and making non-criticalvariations,3-benzyl-9-[(4-trifluoromethyl)phenyl]sulfonyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 7) is converted to the title compound, mp=286°, dec.; IR(drift) 2740, 2716, 1321, 1309, 1187, 1172, 1155, 1132,1109, 1098, 1063,845, 719, 648 and 625 cm⁻¹; NMR (300 MHz, DMSO-d₆) 9.31, 8.19, 8.13,7.93, 7.64, 3.71 and 3.10-3.40 δ.

Example 126-Ethyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

Following the general procedure of EXAMPLE 8, and making non-criticalvariations,3-benzyl-9-[(4-trifluoromethylphenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 7) is converted to the title compound, mp=170-179°, dec.; IR(drift) 2762, 1326, 1302, 1294, 1190, 1184, 1171, 1153, 1138, 1109,1095, 1064, 830, 716 and 618 cm⁻¹; NMR (300 MHz, DMSO-d₆) 9.40, 8.20,8.14, 7.93, 7.65, 4.15-4.30, 3.10-3.45 and 1.10-1.20 δ.

Example 136-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

Step I: 1-Benzoyl-4-azepanone N-[4-(phenylsulfonyl)phenyl]hydrazone

A mixture of 1-[4-(phenylsulfonyl)phenyl]hydrazine (2.05 g, 8.26 mmol)and 4-benzoylazapanone (1.97 g, 9.09 mmol) in ethanol (40 mL) is treatedwith glacial acetic acid (8 drops) and heated at reflux for 1 hr. Uponcooling, the precipitate is collected, washed with ethanol and dried inthe vacuum oven (50°) to give the desired hydrazone, mp=202-204°.

Step II:3-Benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

A mixture of 1-benzoyl-4-azepanone N-[4-(phenylsulfonyl)phenyl]hydrazone(Step I, 2.00 g, 4.47 mmol) in dichloroethane/phosphoric acid 84% (1/1,40 mL) is heated at reflux for 16 hr. Upon cooling, the product isdiluted with saline and extracted into methylene chloride (3×). Theextracts are dried, filtered, and concentrated under reduced pressure togive a solid. The solid is purified via silica gel chromatography(Biotage 40M; ethyl acetate/heptane, 75/25) to give the desired indole.

Step III:3-Benzoyl-6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4.5-b]indole

A 0° mixture of3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Step II, 1.61 g, 3.74 mmol) in dry DMF (18 mL) is treated with sodiumhydride (60% in oil, 165 mg, 4.11 mmol). After 30 min, the mixture istreated with iodomethane (256 μL, 4.11 mmol) and allowed to slowly warmto 20-25° under nitrogen over 16 hr. The resultant mixture is dilutedwith H₂O and filtered. The residual solid is triturated with refluxingmethanol, isolated, and dried in the vacuum oven at 50° to give thedesired indole, imp=254-255°.

Step IV:6-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

A mixture of3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(Step III, 1.25 g, 2.81 mmol) and potassium hydroxide (1.58 g, 28.1mmol) in ethylene glycol (30 mL) is heated at 130° under nitrogen for 92hr. Upon cooling, the mixture is diluted with H₂O and extracted intoethyl acetate (3×). The combined extracts are washed with H₂O (2×) andsaline, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to give a solid. The solid isdissolved in hot methylene chloride/methanol and treated with methanolichydrochloric acid. The resultant mixture is concentrated andcrystallized from ethyl acetate/methanol to give the title compound,mp>300°; IR (drift) 2820, 2792, 2747, 2717, 2704, 2665, 2651, 1299,1147, 1096, 803, 729, 687, 643 and 621 cm⁻¹; NMR (300 MHz, DMSO-d₆)9.41, 8.13, 7.85-7.95, 7.50-7.65, 3.70 and 3.10-3.40 δ; MS (EI) m/z 340(M⁺), 298, 157, 156, 128, 78, 74, 73, 58 and 57; HRMS (FAB) calculatedfor C₁₉H₂₁N₂O₂S=341.1324, found=341.1319.

Example 149-[(3,4-Difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

Following the general procedure of EXAMPLE 1 (steps I-III) and makingnon-critical variations,1-[4-[(3,4-difluorophenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2)is converted to the title compound, mp=320°, dec; IR (drift) 2732, 1507,1310, 1293, 1277, 1147, 1128, 1116, 1072, 800, 751, 686, 627, 622 and610 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ 11.75, 9.50, 8.10-8.20, 7.75-7.85,7.55-7.70, 7.40-7.50, 3.25-3.40 and 3.10-3.25; OAMS (supporting ionsat): ESI+363.1, ESI−361.0.

Example 159-[(3,5-Difluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(IX)

Following the general procedure of EXAMPLE 1 (steps I-III) and makingnon-critical variations,1-[4-[(3,5-difluorophenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2)is converted to the title compound, mp=313-315°, dec; IR (drift) 3256,1606, 1591, 1307, 1285, 1269, 1153, 1138, 1122, 983, 850, 795, 678, 666and 618 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ 11.70, 9.35, 8.15-8.25, 7.40-7.85and 3.10-3.40; MS (EI) m/z 362 (M⁺), 333, 320, 154, 142, 127, 115, 113,92 and 63.

Example 169-[(3,5-Difluorophenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

Following the general procedure of EXAMPLE 13 (steps I-IV) and makingnon-critical variations,1-[4-[(3,5-difluorophenyl)sulfonyl]phenyl]hydrazine (V, PREPARATION 2)(EXAMPLE 2) is converted to the title compound, mp=337-340°, dec; IR(drift) 2767, 2750, 1603, 1437, 1308, 1295, 1144, 1129, 988, 807, 709,681, 675, 650 and 627 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ 9.35, 8.20-8.30,7.60-7.80, 3.71 and 3.15-3.45; MS (EI) m/z 376 (M⁺), 334, 334, 156, 114,113, 64, 63, 57, 52 and 51; HRMS (FAB) calculated forC₁₉H₁₉F₂N₂O₂S=377.1135, found=377.1125.

Example 179-[(4-(2-Hydroxyethoxy)phenyl)sulfonyl]-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (IX)

Following the general procedure of EXAMPLE 13 (steps I-IV) and makingnon-critical variations, 1-[4-[(4-fluorophenyl)sulfonyl]phenyl]hydrazine(V, PREPARATION 2) is converted to the title compound, mp=285-287°, dec;IR (drift) 2957, 2835, 2811, 2760, 1592, 1492, 1458, 1309, 1293, 1261,1142, 1092, 721, 637 and 618 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ 9.43, 8.09,7.81, 7.57, 7.06, 4.85-4.95, 3.95-4.05, 3.69 and 3.00-3.45; MS (EI) m/z400 (M⁺), 86, 84, 77, 73, 72, 71, 58, 57, 56 and 51; HRMS (FAB)calculated for C₂₁H₂₅N₂O₄S=401.1535, found=401.1540.

Example 183,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(X)

A mixture of6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 13, 341 mg, 1.00 mmol) in acetonitrile (5 mL) is treated withformaldehyde (37%, 0.400 mL, 5.00 mmol), sodium cyanoborohydride (101mg, 1.60 mmol) and glacial acetic acid (1 drop). After 5 hr, the mixtureis diluted with ethyl acetate and then washed with water and saline. Theorganic layer is dried, filtered, and concentrated. The concentrate isdissolved in methylene chloride/methanol and treated with methanolichydrochloric acid. The solvent is then removed and the residual solidcrystallized from hot ethyl acetate/methanol to give the title compound,mp=283-286°; IR (drift) 2523, 2477, 2453, 2428, 1479, 1311, 1304, 1283,1150, 1094, 756, 730, 694, 644 and 623 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ11.00, 8.16, 7.85-7.95, 7.50-7.65, 3.70, 3.15-3.45 and 2.89; MS (FAB)m/z 355 (MH⁺), 354, 353, 58 and 44; HRMS (FAB) calculated forC₂₀H₂₃N₂O₂S=355.1480, found=355.1488.

Example 193-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(X)

Following the general procedure of EXAMPLE 18, and making non-criticalvariations, 9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 1) is converted to the title compound, mp=150°, dec; IR (drift)2623, 1474, 1447, 1338, 1301, 1173, 1152, 1129, 1090, 755, 741, 719,689, 673 and 615 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ 11.68, 8.14, 7.85-7.95,7.40-7.65, 3.10-3.45 and 2.88; MS (EI) m/z 340 (M⁺), 296, 77, 74, 73,72, 71, 58, 57, 56 and 51; HRMS (FAB) calculated forC₁₉H₂₁N₂O₂S=341.1324, found=341.1331.

Example 209-[(4-fluorophenyl)sulfonyl]-3-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(X)

Following the general procedure of EXAMPLE 18, and making non-criticalvariations,6-methyl-9-[(4-fluorophenyl)sulfonyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(EXAMPLE 10)) is converted to the title compound, mp=282-283°, dec; IR(drift) 2479, 2437, 1589, 1490, 1310, 1284, 1239, 1161, 1144, 1092, 838,809, 718, 677 and 667 cm⁻¹; NMR (300 MHz, DMSO-d₆) δ 10.60, 8.17, 7.99,7.62, 7.39, 3.71, 3.10-3.75 and 1.31; MS (EI) m/z 400 (M⁺), 385, 328,315, 169, 167, 127, 85, 71, 70 and 56; HRMS (FAB) calculated forC₂₂H₂₆FN₂O₂S=401.1699, found=401.1709.

Examples 21-44

Following the general procedure of the above EXAMPLEs, makingnon-critical variations and starting with the corresponding appropriatestarting materials, the following compounds are obtained:

-   21.    1-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   22.    2-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   23.    4-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   24.    5-Methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   25.    9-[(4-Fluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   26.    9-[(4-Fluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   27.    9-[(4-Fluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   28.    9-[(4-Fluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   29.    1,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   30.    2,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   31.    4,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   32.    5,6-Dimethyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   33.    9-[(4-Fluorophenyl)sulfonyl]-1,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   34.    9-[(4-Fluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   35.    9-[(4-Fluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   36.    9-[(4-Fluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   37.    9-[(3,5-Difluorophenyl)sulfonyl]-1-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   38.    9-[(3,5-Difluorophenyl)sulfonyl]-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   39.    9-[(3,5-Difluorophenyl)sulfonyl]-4-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   40.    9-[(3,5-Difluorophenyl)sulfonyl]-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   41.    9-[(3,5-Difluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   42.    9-[(3,5-Difluorophenyl)sulfonyl]-2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   43.    9-[(3,5-Difluorophenyl)sulfonyl]-4,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-   44.    9-[(3,5-Difluorophenyl)sulfonyl]-5,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

CHART A

CHART B

CHART C

1. A protected 9-arylsulfone of formula (VIII)

where PG is selected from the group consisting of φ—CH₂—, φ—CO—,φ—CH₂—CO₂— and —CO—O—C(CH₃)₃, where R_(X) is: (1) —H (2) —F, —Cl, —Br,—I, (3) —O—R_(X-1) where R_(X-1) is: —H, C₁-C₄ alkyl, —φ, (4) —CF₃, (5)—CO—NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are —H and C₁-C₄ alkyl,and where R_(X-2) and R_(X-3) are taken with the attached nitrogen atomto form a ring selected from the group consisting of 1-pyrrolidinyl,1-piperazinyl and 1-morpholinyl, (6) —NH—SO₂—R_(X-4) where R_(X-4) is —Hand C₁-C₄ alkyl, (7) —NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are asdefined above, (8) —NR_(X-4)—CO—R_(X-4) where R_(X-4) is as definedabove, (9) —SO₂—NR_(X-2)R_(X-3) where R_(X-2) and R_(X-3) are as definedabove, (10) —C≡N, (11) —NO₂; and where R₉ is: (1) —H, (2) —F, —Cl, (3)C₁-C₄ alkyl, (4) C₁-C₃ alkoxy, (5) —CF₃, (6) C₀-C₄ alkyl-φ where the —φsubstituent is optionally substituted with 1 or 2 (a) —F, —Cl, —Br, —I,(b) —O—R₉₋₁ where R₉₋₁ is: —H, C₁-C₄ alkyl, —φ, (c) —CF₃, (d)—CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are —H and C₁-C₄ alkyl, and where R₉₋₂and R₉₋₃ are taken with the attached nitrogen atom to form a ringselected from the group consisting of 1-pyrrolidinyl, 1-piperazinyl and1-morpholinyl, (e) —NH—SO₂—R₉₋₄ where R₉₋₄ is —H and C₁-C₄ alkyl, (f)—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above, (g) —NR₉₋₄—CO—R₉₋₄where R₉₋₄ is as defined above, (h) —SO₂—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃are as defined above, (i) —C≡N, (j) —NO₂ (7) —OR₉₋₁ where R₉₋₁ is asdefined above, (8) —CO—NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as definedabove, (9) —NR₉₋₂R₉₋₃ where R₉₋₂ and R₉₋₃ are as defined above, (10)—NH—SO₂—R₉₋₄ where R₉₋₄ is as defined above, (11) —NH—CO₂—R₉₋₂ whereR₉₋₂ is as defined above.
 2. A protected 9-arylsulfone according toclaim 1 where PG is φ—CH₂— or φ—CO— and where R₉ is selected from thegroup consisting of —H, —F, —Cl, C₁-C₃ alkyl, C₁-C₃ alkoxy and —CF₃ andwhere R_(X) is selected from the group consisting of —H, —F and —Cl.